5xgn

From Proteopedia

Jump to: navigation, search

Crystal structure of EGFR 696-1022 T790M/C797S in complex with Go6976

Structural highlights

5xgn is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 3Å
Ligands:85X, CL
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

EGFR_HUMAN Defects in EGFR are associated with lung cancer (LNCR) [MIM:211980. LNCR is a common malignancy affecting tissues of the lung. The most common form of lung cancer is non-small cell lung cancer (NSCLC) that can be divided into 3 major histologic subtypes: squamous cell carcinoma, adenocarcinoma, and large cell lung cancer. NSCLC is often diagnosed at an advanced stage and has a poor prognosis.

Function

EGFR_HUMAN Receptor tyrosine kinase binding ligands of the EGF family and activating several signaling cascades to convert extracellular cues into appropriate cellular responses. Known ligands include EGF, TGFA/TGF-alpha, amphiregulin, epigen/EPGN, BTC/betacellulin, epiregulin/EREG and HBEGF/heparin-binding EGF. Ligand binding triggers receptor homo- and/or heterodimerization and autophosphorylation on key cytoplasmic residues. The phosphorylated receptor recruits adapter proteins like GRB2 which in turn activates complex downstream signaling cascades. Activates at least 4 major downstream signaling cascades including the RAS-RAF-MEK-ERK, PI3 kinase-AKT, PLCgamma-PKC and STATs modules. May also activate the NF-kappa-B signaling cascade. Also directly phosphorylates other proteins like RGS16, activating its GTPase activity and probably coupling the EGF receptor signaling to the G protein-coupled receptor signaling. Also phosphorylates MUC1 and increases its interaction with SRC and CTNNB1/beta-catenin.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] Isoform 2 may act as an antagonist of EGF action.[14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26]

Publication Abstract from PubMed

Drug-resistance is a major challenge in targeted therapy of EGFR mutated non-small cell lung cancers (NSCLCs). The third-generation irreversible inhibitors such as AZD9291, CO-1686 and WZ4002 can overcome EGFR T790M drug-resistance mutant through covalent binding through Cys 797, but ultimately lose their efficacy upon emergence of the new mutation C797S. To develop new reversible inhibitors not relying on covalent binding through Cys 797 is therefore urgently demanded. Go6976 is a staurosporine-like reversible inhibitor targeting T790M while sparing the wild-type EGFR. In the present work, we reported the complex crystal structures of EGFR T790M/C797S + Go6976 and T790M + Go6976, along with enzyme kinetic data of EGFR wild-type, T790M and T790M/C797S. These data showed that the C797S mutation does not significantly alter the structure and function of the EGFR kinase, but increases the local hydrophilicity around residue 797. The complex crystal structures also elucidated the detailed binding mode of Go6976 to EGFR and explained why this compound prefers binding to T790M mutant. These structural pharmacological data would facilitate future drug development studies.

Structural pharmacological studies on EGFR T790M/C797S.,Kong LL, Ma R, Yao MY, Yan XE, Zhu SJ, Zhao P, Yun CH Biochem Biophys Res Commun. 2017 Jun 24;488(2):266-272. doi:, 10.1016/j.bbrc.2017.04.138. Epub 2017 Apr 26. PMID:28456628[27]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

Loading citation details..
Citations
2 reviews cite this structure
[Acquired Drug Resistance Mechanism of Osimertinib in the Targeted Therapy of Non-small Cell Lung Cancer].
Zhao et al. (2020)
1 more
7 other articles
No citations found

See Also

References

  1. ↑ Galisteo ML, Dikic I, Batzer AG, Langdon WY, Schlessinger J. Tyrosine phosphorylation of the c-cbl proto-oncogene protein product and association with epidermal growth factor (EGF) receptor upon EGF stimulation. J Biol Chem. 1995 Sep 1;270(35):20242-5. PMID:7657591
  2. ↑ Derrien A, Druey KM. RGS16 function is regulated by epidermal growth factor receptor-mediated tyrosine phosphorylation. J Biol Chem. 2001 Dec 21;276(51):48532-8. Epub 2001 Oct 15. PMID:11602604 doi:10.1074/jbc.M108862200
  3. ↑ Shao H, Cheng HY, Cook RG, Tweardy DJ. Identification and characterization of signal transducer and activator of transcription 3 recruitment sites within the epidermal growth factor receptor. Cancer Res. 2003 Jul 15;63(14):3923-30. PMID:12873986
  4. ↑ Arcaro A, Zvelebil MJ, Wallasch C, Ullrich A, Waterfield MD, Domin J. Class II phosphoinositide 3-kinases are downstream targets of activated polypeptide growth factor receptors. Mol Cell Biol. 2000 Jun;20(11):3817-30. PMID:10805725
  5. ↑ Habib AA, Chatterjee S, Park SK, Ratan RR, Lefebvre S, Vartanian T. The epidermal growth factor receptor engages receptor interacting protein and nuclear factor-kappa B (NF-kappa B)-inducing kinase to activate NF-kappa B. Identification of a novel receptor-tyrosine kinase signalosome. J Biol Chem. 2001 Mar 23;276(12):8865-74. Epub 2000 Dec 14. PMID:11116146 doi:10.1074/jbc.M008458200
  6. ↑ Li Y, Ren J, Yu W, Li Q, Kuwahara H, Yin L, Carraway KL 3rd, Kufe D. The epidermal growth factor receptor regulates interaction of the human DF3/MUC1 carcinoma antigen with c-Src and beta-catenin. J Biol Chem. 2001 Sep 21;276(38):35239-42. Epub 2001 Aug 1. PMID:11483589 doi:10.1074/jbc.C100359200
  7. ↑ Wang SC, Nakajima Y, Yu YL, Xia W, Chen CT, Yang CC, McIntush EW, Li LY, Hawke DH, Kobayashi R, Hung MC. Tyrosine phosphorylation controls PCNA function through protein stability. Nat Cell Biol. 2006 Dec;8(12):1359-68. Epub 2006 Nov 19. PMID:17115032 doi:10.1038/ncb1501
  8. ↑ Hsu JM, Chen CT, Chou CK, Kuo HP, Li LY, Lin CY, Lee HJ, Wang YN, Liu M, Liao HW, Shi B, Lai CC, Bedford MT, Tsai CH, Hung MC. Crosstalk between Arg 1175 methylation and Tyr 1173 phosphorylation negatively modulates EGFR-mediated ERK activation. Nat Cell Biol. 2011 Feb;13(2):174-81. doi: 10.1038/ncb2158. Epub 2011 Jan 23. PMID:21258366 doi:10.1038/ncb2158
  9. ↑ Ogiso H, Ishitani R, Nureki O, Fukai S, Yamanaka M, Kim JH, Saito K, Sakamoto A, Inoue M, Shirouzu M, Yokoyama S. Crystal structure of the complex of human epidermal growth factor and receptor extracellular domains. Cell. 2002 Sep 20;110(6):775-87. PMID:12297050
  10. ↑ Ferguson KM, Berger MB, Mendrola JM, Cho HS, Leahy DJ, Lemmon MA. EGF activates its receptor by removing interactions that autoinhibit ectodomain dimerization. Mol Cell. 2003 Feb;11(2):507-17. PMID:12620237
  11. ↑ Wood ER, Truesdale AT, McDonald OB, Yuan D, Hassell A, Dickerson SH, Ellis B, Pennisi C, Horne E, Lackey K, Alligood KJ, Rusnak DW, Gilmer TM, Shewchuk L. A unique structure for epidermal growth factor receptor bound to GW572016 (Lapatinib): relationships among protein conformation, inhibitor off-rate, and receptor activity in tumor cells. Cancer Res. 2004 Sep 15;64(18):6652-9. PMID:15374980 doi:10.1158/0008-5472.CAN-04-1168
  12. ↑ Red Brewer M, Choi SH, Alvarado D, Moravcevic K, Pozzi A, Lemmon MA, Carpenter G. The juxtamembrane region of the EGF receptor functions as an activation domain. Mol Cell. 2009 Jun 26;34(6):641-51. PMID:19560417 doi:10.1016/j.molcel.2009.04.034
  13. ↑ Lu C, Mi LZ, Grey MJ, Zhu J, Graef E, Yokoyama S, Springer TA. Structural Evidence for Loose Linkage between Ligand Binding and Kinase Activation in the Epidermal Growth Factor Receptor. Mol Cell Biol. 2010 Sep 13. PMID:20837704 doi:10.1128/MCB.00742-10
  14. ↑ Galisteo ML, Dikic I, Batzer AG, Langdon WY, Schlessinger J. Tyrosine phosphorylation of the c-cbl proto-oncogene protein product and association with epidermal growth factor (EGF) receptor upon EGF stimulation. J Biol Chem. 1995 Sep 1;270(35):20242-5. PMID:7657591
  15. ↑ Derrien A, Druey KM. RGS16 function is regulated by epidermal growth factor receptor-mediated tyrosine phosphorylation. J Biol Chem. 2001 Dec 21;276(51):48532-8. Epub 2001 Oct 15. PMID:11602604 doi:10.1074/jbc.M108862200
  16. ↑ Shao H, Cheng HY, Cook RG, Tweardy DJ. Identification and characterization of signal transducer and activator of transcription 3 recruitment sites within the epidermal growth factor receptor. Cancer Res. 2003 Jul 15;63(14):3923-30. PMID:12873986
  17. ↑ Arcaro A, Zvelebil MJ, Wallasch C, Ullrich A, Waterfield MD, Domin J. Class II phosphoinositide 3-kinases are downstream targets of activated polypeptide growth factor receptors. Mol Cell Biol. 2000 Jun;20(11):3817-30. PMID:10805725
  18. ↑ Habib AA, Chatterjee S, Park SK, Ratan RR, Lefebvre S, Vartanian T. The epidermal growth factor receptor engages receptor interacting protein and nuclear factor-kappa B (NF-kappa B)-inducing kinase to activate NF-kappa B. Identification of a novel receptor-tyrosine kinase signalosome. J Biol Chem. 2001 Mar 23;276(12):8865-74. Epub 2000 Dec 14. PMID:11116146 doi:10.1074/jbc.M008458200
  19. ↑ Li Y, Ren J, Yu W, Li Q, Kuwahara H, Yin L, Carraway KL 3rd, Kufe D. The epidermal growth factor receptor regulates interaction of the human DF3/MUC1 carcinoma antigen with c-Src and beta-catenin. J Biol Chem. 2001 Sep 21;276(38):35239-42. Epub 2001 Aug 1. PMID:11483589 doi:10.1074/jbc.C100359200
  20. ↑ Wang SC, Nakajima Y, Yu YL, Xia W, Chen CT, Yang CC, McIntush EW, Li LY, Hawke DH, Kobayashi R, Hung MC. Tyrosine phosphorylation controls PCNA function through protein stability. Nat Cell Biol. 2006 Dec;8(12):1359-68. Epub 2006 Nov 19. PMID:17115032 doi:10.1038/ncb1501
  21. ↑ Hsu JM, Chen CT, Chou CK, Kuo HP, Li LY, Lin CY, Lee HJ, Wang YN, Liu M, Liao HW, Shi B, Lai CC, Bedford MT, Tsai CH, Hung MC. Crosstalk between Arg 1175 methylation and Tyr 1173 phosphorylation negatively modulates EGFR-mediated ERK activation. Nat Cell Biol. 2011 Feb;13(2):174-81. doi: 10.1038/ncb2158. Epub 2011 Jan 23. PMID:21258366 doi:10.1038/ncb2158
  22. ↑ Ogiso H, Ishitani R, Nureki O, Fukai S, Yamanaka M, Kim JH, Saito K, Sakamoto A, Inoue M, Shirouzu M, Yokoyama S. Crystal structure of the complex of human epidermal growth factor and receptor extracellular domains. Cell. 2002 Sep 20;110(6):775-87. PMID:12297050
  23. ↑ Ferguson KM, Berger MB, Mendrola JM, Cho HS, Leahy DJ, Lemmon MA. EGF activates its receptor by removing interactions that autoinhibit ectodomain dimerization. Mol Cell. 2003 Feb;11(2):507-17. PMID:12620237
  24. ↑ Wood ER, Truesdale AT, McDonald OB, Yuan D, Hassell A, Dickerson SH, Ellis B, Pennisi C, Horne E, Lackey K, Alligood KJ, Rusnak DW, Gilmer TM, Shewchuk L. A unique structure for epidermal growth factor receptor bound to GW572016 (Lapatinib): relationships among protein conformation, inhibitor off-rate, and receptor activity in tumor cells. Cancer Res. 2004 Sep 15;64(18):6652-9. PMID:15374980 doi:10.1158/0008-5472.CAN-04-1168
  25. ↑ Red Brewer M, Choi SH, Alvarado D, Moravcevic K, Pozzi A, Lemmon MA, Carpenter G. The juxtamembrane region of the EGF receptor functions as an activation domain. Mol Cell. 2009 Jun 26;34(6):641-51. PMID:19560417 doi:10.1016/j.molcel.2009.04.034
  26. ↑ Lu C, Mi LZ, Grey MJ, Zhu J, Graef E, Yokoyama S, Springer TA. Structural Evidence for Loose Linkage between Ligand Binding and Kinase Activation in the Epidermal Growth Factor Receptor. Mol Cell Biol. 2010 Sep 13. PMID:20837704 doi:10.1128/MCB.00742-10
  27. ↑ Kong LL, Ma R, Yao MY, Yan XE, Zhu SJ, Zhao P, Yun CH. Structural pharmacological studies on EGFR T790M/C797S. Biochem Biophys Res Commun. 2017 Jun 24;488(2):266-272. doi:, 10.1016/j.bbrc.2017.04.138. Epub 2017 Apr 26. PMID:28456628 doi:http://dx.doi.org/10.1016/j.bbrc.2017.04.138

Contents


PDB ID 5xgn

Drag the structure with the mouse to rotate

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://proteopedia.org/wiki/index.php/5xgn"
Personal tools